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Published online June 2, 2008
Diabetes 57:2272-2279, 2008
DOI: 10.2337/db08-0477
© 2008 by the American Diabetes Association
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Pyruvate Dehydrogenase Kinase 4

Regulation by Thiazolidinediones and Implication in Glyceroneogenesis in Adipose Tissue

Thomas Cadoudal, Emilie Distel, Sylvie Durant, Françoise Fouque, Jean-Marc Blouin, Martine Collinet, Sylvie Bortoli, Claude Forest, and Chantal Benelli

From the Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-S 747, Université Paris Descartes, Centre Universitaire des Saints-Pères, Paris, France

Corresponding author: Dr. Claude Forest, claude.forest{at}univ-paris5.fr

OBJECTIVE—Pyruvate dehydrogenase complex (PDC) serves as the metabolic switch between glucose and fatty acid utilization. PDC activity is inhibited by PDC kinase (PDK). PDC shares the same substrate, i.e., pyruvate, as glyceroneogenesis, a pathway controlling fatty acid release from white adipose tissue (WAT). Thiazolidinediones activate glyceroneogenesis. We studied the regulation by rosiglitazone of PDK2 and PDK4 isoforms and tested the hypothesis that glyceroneogenesis could be controlled by PDK.

RESEARCH DESIGN AND METHODS—Rosiglitazone was administered to Zucker fa/fa rats, and then PDK4 and PDK2 mRNAs were examined in subcutaneous, periepididymal, and retroperitoneal WAT, liver, and muscle by real-time RT-PCR. Cultured WAT explants from humans and rats and 3T3-F442A adipocytes were rosiglitazone-treated before analyses of PDK2 and PDK4 mRNA and protein. Small interfering RNA (siRNA) was transfected by electroporation. Glyceroneogenesis was determined using [1-14C]pyruvate incorporation into lipids.

RESULTS—Rosiglitazone increased PDK4 mRNA in all WAT depots but not in liver and muscle. PDK2 transcript was not affected. This isoform selectivity was also found in ex vivo–treated explants. In 3T3-F442A adipocytes, Pdk4 expression was strongly and selectively induced by rosiglitazone in a direct and transcriptional manner, with a concentration required for half-maximal effect at 1 nmol/l. The use of dichloroacetic acid or leelamine, two PDK inhibitors, or a specific PDK4 siRNA demonstrated that PDK4 participated in glyceroneogenesis, therefore altering nonesterified fatty acid release in both basal and rosiglitazone-activated conditions.

CONCLUSIONS—These data show that PDK4 upregulation in adipocytes participates in the hypolipidemic effect of thiazolidinediones through modulation of glyceroneogenesis.


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